Remission and response to early treatment of RA assessed by the Disease Activity Score

B. Svensson, C. Schaufelberger1, A. Teleman and J. Theander2 for the BARFOT study group

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


    Abstract
 Top
 Abstract
 Introduction
 Description of the study...
 Present investigation
 Results
 Discussion
 References
 
Objective. To assess criteria for individual response and remission based on the Disease Activity Score (DAS) in patients with RA participating in a long-term observational study.

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.


    Introduction
 Top
 Abstract
 Introduction
 Description of the study...
 Present investigation
 Results
 Discussion
 References
 
The primary objective in the treatment of rheumatoid arthritis (RA) is, in most hands, suppression of the inflammatory process with disease modifying anti-rheumatic drugs (DMARDs) and with the recently introduced biologicals, such as inhibitors of tumour necrosis factor {alpha}, often in combination with corticosteroids. DMARD treatment given to patients with early disease has resulted in significant reduction in radiographic progression [1]. However, although some retarding effect on joint destruction has been claimed for most DMARDs, many studies show X-ray progression in spite of clinical improvement [2].

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.


    Description of the study from which the patients were recruited
 Top
 Abstract
 Introduction
 Description of the study...
 Present investigation
 Results
 Discussion
 References
 
BARFOT observational study
The BARFOT (Better Anti-rheumatic Farmacotherapy) study is a long-term multicentre observational study of patients with early RA in southern Sweden. As of spring 1999, about 1200 patients are included. Participating rheumatology units are second referrals with well-developed contacts with the primary health-care units in the referral area. All available patients with a diagnosis of rheumatoid arthritis according to the 1987 revised ACR criteria [9] are included, provided they are seen within 1 yr of first definite symptom or sign of synovitis. The patients are followed at predetermined intervals using a structured protocol of validated variables reflecting disease activity, joint destruction, function and overall health.

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 5–15 mg in addition to the lowest possible dose of PRE, or (strategy 2) sulphasalazine (SAL) 2–3 g daily or auranofin (AUR) 6–9 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).


    Present investigation
 Top
 Abstract
 Introduction
 Description of the study...
 Present investigation
 Results
 Discussion
 References
 
Patients
Only the first 90 of the 187 patients participating in the randomized treatment study could be included in the present study of response and remission, as the DAS28 was substituted for the original DAS in the assessment of the subsequent patients, giving a different range of scores.

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:

1. The DAS [7], a validated composite index of inflammation integrating in a continuous variable the erythrocyte sedimentation rate, the number of swollen joints, the Ritchie index and the patient's assessment of disease activity (‘patient global health’) on a 0–100 mm horizontal visual analogue scale (VAS).
2. Posterior–anterior X-rays of the hands and forefeet. A Larsen score [10] could be computed in 68 patients at baseline and in 69 after 2 yr (mean of the scores obtained by two independent readers).
3. The validated Swedish version [11] of the Stanford Health Assessment Questionnaire (HAQ), an instrument for the self-assessment of daily life function. Pain was assessed with a 0–100 mm horizontal VAS.

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. 1Go).



View larger version (16K):
[in this window]
[in a new window]
 
FIG. 1. EULAR criteria for individual response [3]. Response (good or moderate) is defined as a change (improvement) in DAS from baseline in relation to end-point DAS.

 
A patient was considered as being in remission if he or she had a DAS <1.6 after 2 yr of treatment [6].

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 Mann–Whitney and Kruskal–Wallis tests were used for between-group comparisons, the Wilcoxon signed ranks test for paired samples and the {chi}2 test for differences between proportions.


    Results
 Top
 Abstract
 Introduction
 Description of the study...
 Present investigation
 Results
 Discussion
 References
 
Individual response and remission
At baseline, the mean DAS was 4.0 (Fig. 2Go). Eighty-one of the 90 patients (90%) had a DAS >2.4, which has been found to be consistent with active disease [13], while the remaining nine patients had a DAS ranging from 1.7 to 2.25. Thus, at inclusion in the study most patients had active disease and none was in remission according to the criteria used.



View larger version (40K):
[in this window]
[in a new window]
 
FIG. 2. Distribution of DAS at baseline. DAS <1.6 indicates remission [6] and <= 2.4 indicates low disease activity. DAS >2.4 and <= 3.7 indicates moderate disease activity; DAS >3.7 indicates high disease activity [3].

 
After 2 yr (Fig. 3Go) the mean DAS was 2.4 and had decreased significantly (P < 0.001) compared with baseline.



View larger version (39K):
[in this window]
[in a new window]
 
FIG. 3. Distribution of DAS after 2 yr of treatment. DAS <1.6 indicates remission [6] and <= 2.4 indicates low disease activity. DAS >2.4 and <= 3.7 indicates moderate disease activity; DAS >3.7 indicates high disease activity [3].

 
According to the EULAR criteria, 68 (76%) of the 90 patients were judged to be responders after 2 yr of treatment. Forty-one patients had a good response (46%) and 27 had a moderate response (30%); 22 were classified as non-responders (24%). The rates of EULAR response were similar in the two treatment groups (–76% in S1 and 73% in S2). The distribution of moderate and good responders was also similar in the two treatment groups (P = 0.821).

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 1Go) 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.


View this table:
[in this window]
[in a new window]
 
TABLE 1. Radiological progression in good responders, moderate responders and non-responders, in responders with different levels of end-point disease activity, and in patients in remission and not in remission. Comparisons of available pairs of Larsen scores before and after 2 yr of treatment

 
Twenty (29%) of the 68 responders had a final DAS >2.4, i.e. they should be regarded as still having had active disease, albeit to a lesser degree than at baseline. This group of patients had, compared with the remaining 48 responders (41 good and 7 moderate) with a final DAS of <= 2.4, significantly more pain (median 39 vs 8 mm, P < 0.001) and more impaired function (median HAQ score 0.90 vs 0.22, P = 0.009). More interestingly, this group had a significantly higher end-point Larsen score (median 16 vs 3, P = 0.016) while baseline Larsen scores were similar in the two groups of responders (median 2.5 vs 3.5, P = 0.722). Additionally, paired comparisons (Table 1Go) showed significant progression of Larsen scores from baseline to the end-point for responders with a final DAS of >2.4 but not for responders with a final DAS of <= 2.4.

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 1Go) 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.


    Discussion
 Top
 Abstract
 Introduction
 Description of the study...
 Present investigation
 Results
 Discussion
 References
 
To describe individual response and disease remission, criteria based on a continuous variable, the DAS, were used. The EULAR response criteria [3] have recently been found [5] to conform accurately to those proposed by the ACR [4]. Likewise, the remission criterion applied, i.e. DAS <1.6, has been shown [6] to give about the same information as the ACR criteria for remission [8].

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.


    Acknowledgments
 
Supporting grants from the Swedish Arthritis Foundation and from the Vårdalsstiftelsen foundation Stockholm are gratefully appreciated.


    Notes
 
Correspondence to: B. Svensson, Blistorpsvägen 105, S-290 38 V. Vånga, Sweden. Back

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. Back


    References
 Top
 Abstract
 Introduction
 Description of the study...
 Present investigation
 Results
 Discussion
 References
 

  1. Stenger AAME, van Leeuwen MA, Houtman PM et al. Early effective suppression of inflammation in rheumatoid arthritis reduces radiographic progression. Br J Rheumatol1998;37:1157–63.[ISI][Medline]
  2. Mulherin D, Fitzgerald O, Bresnihan B. Clinical improvement and radiological deterioration in rheumatoid arthritis: evidence that the pathogenesis of synovial inflammation and articular erosion may differ. Br J Rheumatol1996;35:1263–8.[ISI][Medline]
  3. Van Gestel AM, Prevoo MLL, van't Hof MA, van Rijswijk MH, van de Putte LB, van Riel PLCM. Development and validation of the European League Against Rheumatism response criteria for rheumatoid arthritis. Arthritis Rheum1996;39:34–40.[Medline]
  4. Felson DT, Anderson JJ, Boers M et al. American College of Rheumatology preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum1995;38:727–35.[ISI][Medline]
  5. Van Gestel AM, Anderson JJ, van Riel PLCM et al. ACR and EULAR improvement criteria have comparable validity in rheumatoid arthritis trials. J Rheumatol1999;26:705–11.[ISI][Medline]
  6. Prevoo MLL, van Gestel AM, van't Hof MA, van Rijswijk MH, van de Putte LBA, van Riel PLCM. Remission in a prospective study of patients with rheumatoid arthritis. American Rheumatism Association preliminary remission criteria in relation to the disease activity score. Br J Rheumatol1996;35:1101–5.[ISI][Medline]
  7. Van der Heijde DMFM, van't Hof MA, van Riel PLCM et al. Judging disease activity in clinical practice in rheumatoid arthritis: first step in the development of a disease activity score. Ann Rheum Dis1990;49:916–20.[Abstract]
  8. Pinals RS, Masi AT, Larsen RA. Preliminary criteria for clinical remission in rheumatoid arthritis. Arthritis Rheum1981;24:1308–15.[ISI][Medline]
  9. Arnett FC, Edworthy SM, Bloch DA et al. The American Rheumatism Association revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum1988;31:315–24.[ISI][Medline]
  10. Larsen A, Dale K. Standardised radiographic evaluation of rheumatoid arthritis in therapeutic trials. In: Dumonde DC, Jasani JK, eds. Recognition of anti-rheumatic drugs. Lancaster: MTP Press 1978:285.
  11. Ekdahl C, Eberhardt K, Andersson SI, Svensson B. Assessing disability in patients with rheumatoid arthritis. Scand J Rheumatol1988;17:263–71.[ISI][Medline]
  12. SPSS Base 9.0 Applications Guide. Chicago, IL: SPSS Inc, 1997.
  13. Van Gestel AM, Haagsma CJ, van Riel PLCM. Validation of rheumatoid arthritis improvement criteria that include simplified joint counts. Arthritis Rheum1998;41:1845–50.[ISI][Medline]
  14. Dougados M, Combe B, Cantagrel A et al. Combination therapy in early rheumatoid arthritis: a randomised, controlled, double blind 52 week clinical trial of sulphasalazine and methotrexate compared with the single components. Ann Rheum Dis1999;58:220–5.[Abstract/Free Full Text]
  15. Möttönen T, Paimela L, Leirisalo-Repo M, Kautiainen H, Ilonen J, Hannonen P. Only high disease activity and positive rheumatoid factor indicate poor prognosis in patients with early rheumatoid arthritis treated with ‘sawtooth' strategy. Ann Rheum Dis1998;57:533–9.[Abstract/Free Full Text]
  16. Teir J, Gray J, Pendelbury A, Grennan DM. Outcome in patients with early rheumatoid arthritis over a two year period. Ann Rheum Dis1999;58:323.[Free Full Text]
  17. Möttönen T, Hannonen P, Leirisalo-Repo M et al. Comparison of combination therapy with single drug therapy in early rheumatoid arthritis: a randomised trial. Lancet1999;353:1568–73.[ISI][Medline]
  18. Harrison BJ, Symmons PM, Brennan P, Barrett EM, Silman AJ. Natural remission in inflammatory polyarthritis: Issues of definition and prediction. Br J Rheumatol1996;35:1096–100.[ISI][Medline]
Submitted 18 August 1999; revised version accepted 17 March 2000.