Spenshult's Hospital for Rheumatic Diseases and Rehabilitation, Halmstad,
1 Department of Rheumatology, Sahlgrenska University Hospital, Mölndal and
2 Rheumatology Section, Kristianstad County Hospital, Kristianstad, Sweden
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Abstract |
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Methods. The EULAR (European League against Rheumatism) criteria for individual response and a recently proposed remission criterion, DAS <1.6, were applied to 90 patients with RA after treatment for 2 yr with disease-modifying anti-rheumatic drugs (DMARDs) and/or corticosteroids.
Results. Seventy-six per cent of the patients were classified as responders (46% good and 30% moderate responders). Good responders had significantly more improvement in pain and Health Assessment Questionnaire (HAQ) score than moderate responders and non-responders. Paired comparisons showed significant X-ray progression both for moderate responders and non-responders but not for good responders. Twenty-nine per cent of all responders had an end-point DAS >2.4, indicating active disease. In this group of responders, X-ray changes progressed significantly, but this could not be demonstrated in the group of responders with DAS 2.4. Thirty-six per cent of the 90 patients included in the study were classified as being in remission after 2 yr of treatment. The group of patients in remission showed no evidence of X-ray progression after 2 yr.
Conclusions. Response and remission criteria based on DAS were useful in a study of patients with RA who were managed essentially as in clinical practice. The criteria used showed construct and criterion validity, although discriminant validity could not be shown. The application of valid criteria for response and remission in clinical practice may be a useful aid in the evaluation of treatment effects and in making treatment decisions for individual patients.
KEY WORDS: Early rheumatoid arthritis, Individual response criteria, Remission criteria, Disease Activity Score.
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Introduction |
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To assess the outcome of treatment in RA in clinical trials, criteria for individual responses are used increasingly. The current criteria proposed by EULAR (European League Against Rheumatism) [3] and by the American College of Rheumatology (ACR) [4] have been validated recently [5]. The EULAR criteria are based on a significant change in disease activity in relation to the level of disease activity attained, whereas the ACR criteria are based on change only.
Evidently, the ultimate goal of the treatment of RA should be a state of being essentially free from disease manifestations (remission). To define remission (whether or not the patient is still on drugs), Prevoo et al. [6] have recently proposed a criterion which, like the EULAR response criteria, is based on the Disease Activity Score (DAS) [7], a continuous variable. The Prevoo remission criterion has proved to correspond well to the ACR remission criteria [8]. Like the response criteria, the remission criteria do not include any measure of joint destruction.
In daily clinical practice, treatment decisions and efficacy judgements are generally based on the treating physician's general opinion of the disease activity. Valid criteria for response and remission applicable to the individual patient could be a useful aid. The aim of the present investigation was therefore to apply the EULAR criteria for response and the Prevoo criterion for remission to patients with RA participating in a long-term observational study with defined treatment strategies but otherwise managed essentially as in clinical practice.
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Description of the study from which the patients were recruited |
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Randomized treatment study
Within the observational study, an open, controlled study is currently running. This includes 187 patients who, at inclusion, were considered to be in need of DMARDs and who had not previously been treated with such drugs or with corticosteroids.
These 187 patients were randomized to one of two treatment groups, receiving either (strategy 1) 10 mg prednisolone (PRE) for 1 month followed, if needed, by methotrexate (MTX) at a weekly dose of 515 mg in addition to the lowest possible dose of PRE, or (strategy 2) sulphasalazine (SAL) 23 g daily or auranofin (AUR) 69 mg daily. In addition, PRE at up to 10 mg daily could be added at any time if needed, with the intention of gradually reducing the dose as soon as possible. Change of therapy is based on the treating physician's judgement without knowledge of the current DAS value.
The general results of this study are out of the scope of this paper and will be reported elsewhere (B. Svensson, in preparation).
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Present investigation |
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Forty-six of the 90 patients were randomized to strategy 1 (S1) and 44 to strategy 2 (S2). The patients had a mean age of 54 yr, 67% were women, and the mean disease duration at inclusion was 6 months.
Treatments
According to the protocol, all S1 patients received initial treatment for 1 month with 10 mg PRE daily. For 28 patients, MTX was added. Twenty (72%) of these were still on MTX after 2 yr and only four had been changed to another DMARD. Forty-one of the 44 S2 patients were started on SAL and three on AUR. After 2 yr, only nine patients in this treatment group (22%) remained on their initial DMARD. Twenty-two patients had been changed to another DMARD, which in 12 cases was MTX.
Thus, after 2 yr the SAL/AUR group (S2) had become similar to the MTX group (S1) with respect to DMARD use, although significantly more patients in S1 than in S2 were still being treated with PRE.
Methods
The following measurements were made at baseline and follow-up:
Definition of individual response and remission.
A patient was judged as a responder (moderate or good) by the EULAR response criteria [3] for rheumatoid arthritis, provided the DAS had reached a certain level of change from the start of the study in relation to the score attained. A decrease in DAS by >1.2 in combination with an end-point DAS of 2.4 defined a good responder, while a moderate responder must have had a DAS that either (i) decreased by >1.2, having attained any DAS >2.4, or (ii) decreased by <1.2, or by >0.6 in combination with an end-point DAS not exceeding 3.7 (Fig. 1
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Validation of response criteria.
Essentially as described by van Gestel et al. [3], criterion validity was assessed by the association between response and clinical aspects of the disease status, such as pain and function (HAQ), and construct validity was assessed by the association between response and radiographic progression, assumed to reflect biologic outcome. Discriminate validity was assessed from a possible difference in the proportions of responders to the two treatment strategies.
Statistical methods.
Statistical analysis was performed using SPSS software [12]. The MannWhitney and KruskalWallis tests were used for between-group comparisons, the Wilcoxon signed ranks test for paired samples and the 2 test for differences between proportions.
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Results |
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By the criteria used, 32 of the 90 patients (36%) were in remission after 2 yr of treatment [18 from S1 and 14 from S2 (P = 0.469)]. Fourteen were on DMARDs and 14 on low-dose corticosteroids (eight were receiving both types of drug). The daily corticosteroid dose exceeded 5 mg in only two cases. All patients in remission were also responders (30 good and two moderate), which means that their disease activity had significantly decreased from baseline to the end-point after 2 yr.
Characterization of responders
Good responders were older (mean age 57 yr) than moderate responders (54 yr) and non-responders (49 yr), although these differences were not statistically significant (P = 0.089). The mean disease duration at inclusion was 6 months in all groups.
Sixty per cent of the men and 38% of the women were good responders, 20 and 35%, respectively, were moderate responders and 20 and 27% were non-responders, but these differences were not statistically significant (P = 0.141). Sixty-two per cent of the patients had rheumatoid factor; there were no differences between the groups (0.197).
There were no baseline differences between the three response groups in the median DAS (P = 0.353), pain VAS (P = 0.784) or HAQ score (P = 0.121). The three groups had similar median Larsen scores (P = 0.186) at inclusion.
After 2 yr of treatment there were significant differences between good responders, moderate responders and non-responders in DAS (median 1.15, 2.31 and 3.24, respectively, P < 0.001), pain (median 8, 32 and 45 mm, P < 0.001) and HAQ score (median 0.13, 0.80 and 1.30, P < 0.001).
Paired comparisons (Table 1) showed significant progression of Larsen score from baseline to the end-point at 2 yr for moderate responders and non-responders but not for good responders.
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Characterization of patients in remission
The mean age (57 yr) of the 32 remitters was higher than that (53 yr) of non-remitters, although the difference was not statistically significant (P = 0.207). The mean disease duration at inclusion was six months in both groups. Fifty-seven per cent of the men (17 of 30) and 25% of the women (15 of 60) were in remission after 2 yr, and this difference was statistically significant (P = 0.003). Sixty-two per cent of the patients had rheumatoid factor, with no difference between the groups (P = 0.312).
At baseline, the group of patients who went into remission, compared with the group who did not, had a lower DAS (median 3.45 vs 4.13, P = 0.025) and HAQ score (median 0.73 vs 1.1, P = 0.006) but there was no difference in pain VAS score (P = 0.954). The baseline median Larsen scores were similar (P = 0.257).
After 2 yr of treatment, the median values for DAS, pain and HAQ score were all highly significantly lower among remitters than among non-remitters (median DAS 0.92 for remitters vs 2.87 for non-remitters; median pain 7 vs 33 mm; median HAQ score 0.0 vs 0.88; P < 0.001 for all three variables).
For patients in remission, paired comparisons (Table 1) showed no significant change in Larsen scores from baseline to the end-point at 2 yr. However, for patients not in remission a significant increase was noted.
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Discussion |
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The patients included in the present study were all part of a cohort of patients with recent RA considered to be in need of DMARD treatment but previously not treated with such drugs or with corticosteroids. Data from 90 of these patients showed that after 2 yr of treatment 76% were judged to be responders (good or moderate). This figure is in fair agreement with those of other studies on DMARDs, e.g. a recent 52-week trial of sulphasalazine, MTX and a combination of them in early disease by Dougados et al. [14] found a EULAR response of 68, 63 and 72% for the three treatments, respectively.
By the criterion used, 36% of the patients in the present study were in remission after 2 yr of treatment. This figure is difficult to compare since, to our knowledge, no other studies have used this criterion. However, Möttönen et al. [15], using the ACR remission criteria, recently found a 27% remission rate for patients receiving DMARD monotherapy in a 2-yr study on early RA. A similar figure, 28%, was reported recently in another study on early RA, by Teir et al. [16]. Furthermore, in another 2-yr study on patients with early RA, Möttönen et al. [17] found a 38% remission rate on DMARD combination treatment whereas only 18% of patients went into remission on DMARD monotherapy.
It is of interest to note that men tended to have a higher rate of good responses than women and that men fulfilled the remission criterion significantly more frequently than women. This is in agreement with the data of others. Thus, in the study by Möttönen et al. [15], male patients went into remission significantly more often than women. Likewise, Harrison et al. [18] found that male gender was one of three predictors of remission 2 yr after a diagnosis of inflammatory polyarthritis.
In agreement with the data of van Gestel et al. [3], the EULAR response criteria applied to this patient population show criterion validity in demonstrating significant associations with pain and function. Discriminant validity could not be ascertained since the response rates were similar in the two treatment groups, probably because a significant number of patients in strategy 2 were changed to MTX, making the the two treatment groups similar in their use of DMARDs. As to construct validity, good responders did not show evidence of significant radiological progression, whereas this was the case for both moderate responders and non-responders.
A corresponding validation procedure for the remission criteria showed criterion and construct but not discriminant validity, since no statistically significant difference in remission rates between the two treatments was observed.
It should be noted that 29% of the patients who were classified as responders had an end-point DAS after treatment of >2.4, indicating moderate or high remaining disease activity. These 20 patients (moderate responders) had, compared with responders with a DAS of 2.4 (41 good and seven moderate responders), significantly more pain and more impaired function. Importantly, in this group of responders significant X-ray progression occurred, while there was no evident progression in the group of responders having a final DAS not higher than 2.4. Since an individual classified as a moderate responder apparently may or may not have important ongoing disease activity, this response category may be ambiguous and difficult to interpret in a clinical setting. Perhaps it could be omitted, allowing only one response category, which would include the present good responders and those moderate responders who have a final DAS not higher than 2.4, a level that has been shown to reflect DMARD treatment decisions made by rheumatologists [3]. In this context it should be mentioned that the ACR improvement criteria [4] only measure change and do not consider the actual disease activity at the end-point.
To conclude, the present data show that response and remission criteria based on the DAS were also useful in a study of patients participating in an observational study with defined treatment strategies but otherwise managed essentially as in daily clinical practice. The criteria used showed construct and criterion validity, but discriminant validity could not be shown because there were similar response rates in the two treatment groups. The application of valid criteria for response and remission in clinical practice could be a useful aid in the evaluation of treatment effects and in making treatment decisions for the individual patient with rheumatoid arthritis.
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Acknowledgments |
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Notes |
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M. Ahlmén, I. Hafström, C. Keller, I. Leden, B. Lindell, I. Petersson, D. Sahlberg, C. Schaufelberger, L. Sköldstam, B. Svensson, A. Teleman and J. Theander.
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References |
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